Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• This invention relates to a jelly composition containing a polyunsaturated fatty acid as a pharmaceutical component together with a second pharmaceutical component, which is convenient and easy to take and which is highly stable. More specifically, this invention relates to a pharmaceutical composition.
• a polyunsaturated fatty acid is defined as a fatty acid including two or more carbon-carbon double bonds in one molecule, and the polyunsaturated fatty acids are categorized by the position of the double bond into ⁇ 3 fatty acid, ⁇ 6 fatty acid, and the like.
• the ⁇ 3 polyunsaturated fatty acids include ⁇ -linolenic acid, icosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), and the ⁇ 6 polyunsaturated fatty acids include linoleic acid, ⁇ -linolenic acid, and arachidonic acid.
• Polyunsaturated fatty acids exhibit various actions including antiarteriosclerotic action, platelet aggregation inhibitory action, hypolipidemic action, antiinflammatory action, antitumor action, and central action, and therefore, polyunsaturated fatty acids are incorporated in various foods, or sold as a health food or pharmaceutical product.
• EPA-E ethyl icosapentaenoate
• ASO arteriosclerosis obliterans
• polyunsaturated fatty acid Since polyunsaturated fatty acid is susceptible to oxidation, and peculiar smell develops with the oxidation, the polyunsaturated fatty acid is generally incorporated in a capsule to thereby prevent the oxidation and seal the unpleasant smell. In the meanwhile, several hundred milligrams to several grams of polyunsaturated fatty acid should be taken at one dose to achieve the effect as described above, and this results in the problems of difficulty of taking a large capsule, difficulty of taking many capsules at a time, and the like. Such problems are particularly serious in the case of elderly patients with reduced ability of swallowing.
• the patients who are taking the EPA-E for the hyperlipidemia often suffer from complication with other diseases, and in such a case, they are required to take two or more drugs, and a typical such case is metabolic syndrome.
• metabolic syndrome patients suffer from complication of two or more of hypertension, abnormal glucose tolerance, dyslipidemia, obesity, and the like, and such multiplicity of the risk factors resulted in the higher occurrence of coronary artery diseases, cerebral infarction, and the like. Recently, this attracted public attention.
• the number of patients suffering from the metabolic syndrome is estimated to be as high as 50,000,000, and this has become a social problem. Increase in the number of patients is also feared in Japan where Westernization of the life has occurred.
• metabolic syndrome Treatment of the metabolic syndrome is based on the improvement of lifestyle, and more specifically, on the alimentary therapy and kinesitherapy.
• improvement of the dietary life or the lack of exercise is often difficult in the patients suffering from the "lifestyle-related diseases", and they usually transfer to pharmacotherapy in order to prevent poor prognosis, for example, onset of myocardial infarction or cerebral infarction.
• metabolic syndrome simultaneously involves hypertension, abnormal glucose tolerance, and dyslipidemia, and therefore, the treatment would be based on the administration of a plurality of drugs, and the patients have to take a plurality of drugs for a long period.
• Such patients with reduced swallowing ability often develop pneumonia from aspiration of food or beverage into the trachea.
• Such aspiration is known to occur less frequently in the case of a highly viscous gel or a jelly compared to liquid with low viscosity such as water (see Fujishima, I. "Eating from mouse: Q&A on dysphagia” published from Chuohoki Publishers Co., Ltd. ).
• jelly preparations have recently been developed as pharmaceutical preparations which can be easily taken by patients with low swallowing ability.
• Exemplary such commercially available jelly preparations include Acivir Oral Jelly (manufactured by Teikoku Medix Co.,Ltd.
• Ciloslet Oral Jelly (manufactured by Teikoku Medix Co.,Ltd. and sold by Zeria Pharmaceutical Co., Ltd .) having cilostazol (a therapeutic agent for chronic artery obstruction) incorporated therein, and Pabron Cough Medicine ⁇ Stick Jelly> (manufactured by Teikoku Medix Co.,Ltd. and sold by Taisho Pharmaceutical Co., Ltd .) which is an over-the-counter drug.
• Jelly preparations are known in the art, and examples include the jelly composition having incorporated therein carageenan, locust bean gum, xanthan gum, and phosphate buffer solution together with Chinese medicine bulk (see, for example, Patent Document 1), and a jelly composition having incorporated therein carageenan, carob bean gum, poly(sodium acrylate), and a surfactant together with cilostazol (antiplatelet drug) (see, for example, Patent Document 2).
• a jelly composition containing a polyunsaturated fatty acid and a second pharmaceutical component is neither disclosed nor suggested in such known jelly compositions having a pharmaceutical component incorporated therein.
• a drug containing a transmucosal absorbefacient comprising a polyunsaturated fatty acid and a polymer gel is also disclosed (see, for example, Patent Document 3).
• the polyunsaturated fatty acid and the macromolecule gel are used as an aid (transmucosal absorbefacient) for facilitating absorption of a substance that is not readily absorbed from the digestive tract (for example, insulin) from the mucosa, for example, by rectal administration, and the pharmaceutical and pharmacological action of the polyunsaturated fatty acid itself is neither disclosed nor suggested.
• Patent Document 4 As a preparation containing a second pharmaceutical component together with the polyunsaturated fatty acid, a tablet containing DHA with simvastatin and vitamins has been disclosed (see for example, Patent Document 4). Also disclosed is a method for incorporating a liquid active component in a solid pharmaceutical composition (see for example, Patent Document 5). This document discloses a sachet having a mixture of ⁇ 3 triglyceride and simvastatin filled therein.
• Patent Document 5 This document discloses a sachet having a mixture of ⁇ 3 triglyceride and simvastatin filled therein.
• Patent Document 1 JP 2001-114696 A
• Patent Document 2 JP 2005-82536 A
• Patent Document 3 JP 2000-128805 A
• Patent Document 4 JP 2004-514684 A
• Patent Document 5 JP 2005-508982 A
• An object of the present invention is to provide a jelly composition, and in particular, a pharmaceutical composition containing a polyunsaturated fatty acid which is a pharmaceutical component together with a second pharmaceutical component, which has at least one of the following characteristic features: high convenience for the patient since two or more pharmaceutical components can be taken at a time which also results in high administration compliance; reduced amount of the jelly composition that needs to be taken at a time; improved release of the effective components in the digestive tract; improved absorption of the effective components into the body; improved storage stability of the effective components; improved dispersibility of the effective components in the composition; improved storage stability of the composition; reduced syneresis of the composition; adequate jelly strength so that the composition does not disintegrate during the transportation or before taking but easily disintegrates once taken; handling convenience in the preparation of the composition; portability of the composition; gratification in taking the composition; and effect of reducing the side effects.
• the present invention provides a jelly composition
• a jelly composition comprising a polyunsaturated fatty acid as a first pharmaceutical component; a second pharmaceutical component; an emulsifier; and a gelling agent.
• the jelly composition of the present invention contains a polyunsaturated fatty acid which is a pharmaceutical component together with a second pharmaceutical component.
• This composition is a composition having at least one of the following characteristic features: high convenience for the patient since two or more pharmaceutical components can be taken at a time which also results in high administration compliance; reduced amount of the jelly composition that needs to be taken at a time; improved release of the effective components in the digestive tract; improved absorption of the effective components into the body; improved storage stability of the effective components; improved dispersibility of the effective components in the composition; improved storage stability of the composition; reduced syneresis of the composition; adequate jelly strength so that the composition does not disintegrate during the transportation or before taking but easily disintegrates once taken; handling convenience in the preparation of the composition; portability of the composition; gratification in taking the composition; and effect of reducing the side effects; and more particularly, an orally administered pharmaceutical composition which has such characteristic features.
• a polyunsaturated fatty acid is defined as a fatty acid having two or more carbon-carbon double bonds in the molecule, and the polyunsaturated fatty acids are further grouped by the position of the double bond into ⁇ -3, ⁇ -6, and other polyunsaturated fatty acids.
• Exemplary ⁇ -3 polyunsaturated fatty acids include ⁇ -linolenic acid, EPA, and DHA
• exemplary ⁇ -6 polyunsaturated fatty acids include linoleic acid, ⁇ -linolenic acid, and arachidonic acid.
• the polyunsaturated fatty acid used in the present invention may be either a synthetic or a natural polyunsaturated fatty acid, or a natural oil containing such polyunsaturated fatty acids.
• Synthetic products include those which have been produced by chemical synthesis, and semi-synthetic products which have been produced by microorganisms and then subjected to esterification, ester exchange, or the like.
• the natural products may be either those extracted from a natural oil containing polyunsaturated fatty acids by a known means or those which have been further processed to produce crude products or further purified products.
• Salts of a polyunsaturated fatty acid as well as derivatives such as ester, amide, phospholipid, monoglyceride, diglyceride, and triglyceride of a polyunsaturated fatty acid are also included within the polyunsaturated fatty acid used in the present invention.
• the polyunsaturated fatty acid used in the present invention is preferably an ⁇ 3 polyunsaturated fatty acid, and more preferably, the polyunsaturated fatty acid is at least one member selected from EPA, DHA, and ⁇ -linolenic acid. Still more preferably, the polyunsaturated fatty acid is EPA, DHA, or a mixture thereof, and even more preferably, the polyunsaturated fatty acid is ethyl icosapentate (EPA-E), ethyl docosahexaenoate (DHA-E), or a mixture thereof. Most preferably, the polyunsaturated fatty acid is EPA-E.
• An example of the mixture of EPA-E and DHA-E is Omacor (a soft capsule containing about 46% by weight of EPA-E and about 38% by weight of DHA-E manufactured by Ross Products), which is commercially available in the U.S. and the like as a therapeutic agent for hypertriglyceridemia, and which may be used in the present invention.
• the compositional ratio of the EPA-E/DHA-E is not particularly limited as long as the merits of the present invention are realized.
• the embodiments wherein the polyunsaturated fatty acid is in the form of a purified fish oil as well as the embodiments wherein the polyunsaturated fatty acid is at least one member selected from monoglyceride, diglyceride, and triglyceride.
• the purity of the polyunsaturated fatty acid used in the composition of the present invention namely, content of the polyunsaturated fatty acid in the entire fatty acid is not particularly limited. However, the purity is preferably at least 25% by weight, more preferably at least 50% by weight, still more preferably at least 70% by weight, and even more preferably at least 85% by weight, and most preferably, the purity of the polyunsaturated fatty acid is such that it is substantially free from fatty acid components other than the polyunsaturated fatty acid.
• fatty acid referred in the passage "substantially free from fatty acid components other than the polyunsaturated fatty acid” only designates the fatty acid that functions as an effective component, and fatty acid incorporated, for example, as an emulsifier is not included in the "other fatty acid components”.
• the amount of the polyunsaturated fatty acid used in the present invention is not particularly limited as long as the merits of the present invention are retained.
• the polyunsaturated fatty acid is preferably used in an amount of 10 to 50% by weight, and more preferably, in 15 to 30% by weight in relation to the total amount of the jelly composition, and this amount is adequately determined by considering amount of the jelly composition filled in the container, purity of the polyunsaturated fatty acid, and the like.
• the jelly when the jelly contains 20% by weight of the polyunsaturated fatty acid, 600 mg of the polyunsaturated fatty acid can be taken by taking 3 g of the jelly.
• the polyunsaturated fatty acid should be taken after the meal. In such a case, the patient is already feeling full, and amount of the jelly that should be taken is an important factor in the compliance.
• the amount of the jelly should also be reduced in the case of elderly people with less ability of swallowing as well as in the case of patients who are allowed to take only limited amount of water. Accordingly, industrial value will be improved if oil content in the jelly can be increased.
• the second pharmaceutical component in the composition of the present invention is not particularly limited.
• examples include drugs for central nervous system such as hypnotic sedative drugs, antianxiety drugs, antiepileptic drugs, antipyretic analgesic antiphlogistic drugs, stimulating drugs, psychostimulants, antiparkinsonian drugs, drugs for psychoneurosis, cold remedies, dementia drugs, and other drugs for central nervous system; drugs for peripheral nervous system such as topical anesthetics, skeletal muscle relaxants, drugs for autonomic nerve, and antispastics; drugs for sensory organs such as ophthalmic drugs, otolaryngologic drugs, and drugs for vertigo; drugs for circulatory organs such as cardiotonics, arrhythmia drugs, diuretic drugs, hypotensive agents, vasoconstrictors, vasodilators, antihyperlipidemic agents, and other drugs for circulatory organ; drugs for respiratory organs such as antitussive drugs, expectorants, antitussive expectorants, and bronchodil
• antihyperlipidemic agents include hypotensive agents, vasodilators, antidiabetic agents or glucose tolerance improving agents, antiplatelet drugs, dementia drugs, antiviral drugs, cholagogues, renal disease drugs, drugs for central nervous system, thyroid hormone drugs, vitamin E drugs, and pharmaceuticals based on herbal medicine and Chinese medicine, and the most preferred are antihyperlipidemic agents.
• Exemplary antihyperlipidemic agents include statin drugs (HMG-CoA reductase inhibitors) such as pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, cerivastatin, pitavastatin, and rosuvastatin; fibrates such as bezafibrate and fenofibrate; squalene synthase inhibitor (such as TAK-475); and cholesterol absorption inhibitor (such as ezetimibe).
• statin drugs such as pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin.
• hypotensive agents and vasodilators include angiotensin II receptor antagonists such as candesartan, losartan, valsartan, telmisartan, and olmesartan; angiotensin converting enzyme inhibitors such as enalapril, alacepril, imidapril, quinapril, temocapril, delapril, benazepril, captopril, cilazapril, trandolapril, perindopril, and lisinopril; calcium antagonists such as amlodipine, cilnidipine, nifedipine, nicardipine, azelnidipine, efonidipine, barnidipine, manidipine, nilvadipine, felodipine, benidipine, nisoldipine, and nitrendipine; ⁇ 1 blockers such as doxazosin, bunazo
• angiotensin II receptor antagonists such as candesartan, losartan, valsartan, olmesartan, enalapril, amlodipine, cilnidipine, nifedipine, and/or doxazosin.
• Exemplary antidiabetic agents or glucose tolerance improving agents include ⁇ glucosidase inhibitors such as voglibose and acarbose; biguanide drugs such as metformin and buformin; thiazolidine drugs such as pioglitazone, rosiglitazone, and rivoglitazone; sulfonyl urea drugs such as glimepiride, glibenclamide, and gliclazide; and short acting insulin secretagogues such as mitiglinide and nateglinide.
• ⁇ glucosidase inhibitors such as voglibose and acarbose
• biguanide drugs such as metformin and buformin
• thiazolidine drugs such as pioglitazone, rosiglitazone, and rivoglitazone
• sulfonyl urea drugs such as glimepiride, glibenclamide, and
• ⁇ glucosidase inhibitors biguanide drugs, thiazolidine drugs, and/or short acting insulin secretagogues such as voglibose, metformin, pioglitazone, rosiglitazone, rivoglitazone, mitiglinide, and/or nateglinide.
• Exemplary antiplatelet drugs include ADP receptor antagonists such as aspirin and ticlopidine; PDE inhibitors such as cilostazol; sarpogrelate; and clopidogrel.
• Exemplary dementia drugs include donepezil, and exemplary antiviral drugs include ribabirin.
• Exemplary cholagogues include ursodeoxycholic acid, and exemplary renal disease drugs include dilazep and dipyridamole.
• Exemplary drugs for central nervous system include perphenazine and sulpiride, and exemplary thyroid hormone drugs include levothyroxine.
• Exemplary vitamin E drugs include tocopherol acetate, and drugs based on herbal medicine or Chinese medicine include gosha-jinki-gan extract and hachimijiogan extract.
• the second pharmaceutical component is not limited to a single component, and the second pharmaceutical component may include two or more components showing the same drug efficacy, two or more components showing the different drug efficacies, or a combination thereof.
• Exemplary preferable combinations of the second pharmaceutical component include two or more drugs respectively selected from antihyperlipidemic agent, hypotensive agent, and vasodilator; and antidiabetic agent and glucose tolerance improving agent. More specifically, exemplary combinations include the combination of a statin drug and an angiotensin II receptor antagonist; and a combination of a statin drug and a calcium antagonist.
• the second pharmaceutical component may be either a commercially available component or a component synthesized by any of the methods commonly used in the art. Alternatively, the second pharmaceutical component may be the one prepared by pulverizing a commercially available drug, content of a commercially available capsule with no further processing, or an extract of such pulverized drug or capsule content.
• the second pharmaceutical component in one package of the jelly composition is not particularly limited.
• the second pharmaceutical component is preferably incorporated at 1/10 to 2 times the daily dose, more preferably, at 1/3 to the daily dose, and more preferably, at the daily dose.
• the amount should be adequately reduced.
• the typical content is 1 to 60 mg, and more specifically, 5 to 20 mg in the case of pravastatin, 5 to 20 mg in the case of simvastatin, 20 to 60 mg in the case of fluvastatin, 5 to 40 mg in the case of atorvastatin, 1 to 4 mg in the case of pitavastatin, and 2.5 to 20 mg in the case of rosuvastatin.
• the typical content is 5 to 20 mg in the case of ezetimibe.
• the typical content is 2 to 160 mg, and more specifically, 2 to 12 mg in the case of candesartan, 25 to 100 mg in the case of losartan, 40 to 160 mg in the case of valsartan, and 5 to 40 mg in the case of olmesartan.
• the typical content is 0.25 to 150 mg, and more specifically, 2.5 to 10 mg in the case of enalapril, and in the case of a calcium antagonist, the typical content is 2 to 60 mg, and more specifically, 2.5 to 5 mg in the case of amlodipine, 5 to 20 mg in the case of cilnidipine, and 10 to 40 mg in the case of nifedipine.
• the typical content is 0.3 to 12 mg, and more specifically, 0.5 to 8 mg in the case of doxazosin, and in the case of an ⁇ glucosidase inhibitor, the typical content is 0.2 to 300 mg, and more specifically, 0.2 to 0.9 mg in the case of voglibose.
• the typical content is 30 to 750 mg, and more specifically, 150 to 750 mg in the case of metformin, and in the case of a thiazolidine drug, the typical content is 1 to 45 mg, and more specifically, 15 to 45 mg in the case of pioglitazone, and 2 to 8 mg in the case of rosiglitazone.
• the typical content is 10 to 360 mg, and more specifically, 10 to 30 mg in the case of mitiglinide, and 90 to 360 mg in the case of nateglinide.
• the typical content is 3 to 5 mg in the case of donepezil.
• Exemplary preferable combinations of the polyunsaturated fatty acid (the first pharmaceutical component) and the second pharmaceutical component include: EPA-E and an antihyperlipidemic agent; EPA-E and a statin drug; EPA-E and a hypotensive agent or a vasodilator; EPA-E and an angiotensin II receptor antagonist; EPA-E and a calcium antagonist; EPA-E and an antidiabetic agent or a glucose tolerance improving agent; EPA-E, a statin drug, and a hypotensive agent or a vasodilator; EPA-E, a statin drug, and an antidiabetic agent or a glucose tolerance improving agent; EPA-E, a statin drug, a hypotensive agent or a vasodilator, and an antidiabetic agent or a glucose tolerance improving agent; EPA-E and a dementia drug; a mixture of EPA-E and DHA-E and an antihyperlipidemic agent;
• Examples of the preferable combination and the preferable contents of the polyunsaturated fatty acid (the first pharmaceutical component) and the second pharmaceutical component in one package of the jelly composition include 600 to 900 mg of EPA-E and any one to three members selected from 5 to 20 mg of pravastatin, 5 to 20 mg of simvastatin, 20 to 60 mg of fluvastatin, 5 to 40 mg of atorvastatin, 1 to 4 mg of pitavastatin, 2.5 to 20 mg of rosuvastatin, 5 to 20 mg of ezetimibe, 2 to 12 mg of candesartan, 25 to 100 mg of losartan, 40 to 160 mg of valsartan, 5 to 40 mg of olmesartan, 2.5 to 10 mg of enalapril, 2.5 to 5 mg of amlodipine, 5 to 20 mg of cilnidipine, 10 to 40 mg of nifedipine, 0.5 to 8 mg of doxazosin, 0.2 to 0.9 mg of voglibose, 150 to
• Examples of the more preferable combinations include a combination of 600 mg of EPA-E and 10 mg of pravastatin, a combination of 600 mg of EPA-E and 10 mg of simvastatin, a combination of 600 mg of EPA-E and 10 mg of cilnidipine, a combination of 600 mg of EPA-E and 12 mg of candesartan, a combination of 600 mg of EPA-E and 45 mg of pioglitazone, a combination of 600 mg of EPA-E and 3 mg of donepezil, a combination of 600 mg of EPA-E, 5 mg of atorvastatin, and 5 mg of amlodipine, and a combination of 900 mg of EPA-E, 10 mg of simvastatin, and 0.9 mg of voglibose.
• Content of the second pharmaceutical component in the entire jelly composition is preferably in the range of 0.01 to 20% by weight, and more preferably 0.02 to 10% by weight, and this content may be adequately selected depending on the pharmaceutical component.
• the polyunsaturated fatty acid and the second pharmaceutical component are preferably incorporated such that, when the jelly composition is taken, the polyunsaturated fatty acid and the second pharmaceutical component in the jelly composition are rapidly released into and absorbed from the digestive tract to exert their pharmacological effects.
• the emulsifier incorporated in the jelly composition of the present invention is not particularly limited as long as the merits of the present invention are retained.
• Exemplary emulsifiers include sucrose fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, lecithin, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, propylene glycol fatty acid ester, and a saturated fatty acid containing 12 to 22 carbon atoms.
• These emulsifiers may be used in a content of 0.01 to 20% by weight, preferably 0.05 to 10% by weight, and more preferably 0.1 to 5% by weight in relation to the total amount of the jelly composition.
• sucrose fatty acid ester examples include stearate esters having an HLB of 1 to 5. The most preferred is the one having an HLB of 2 (Surfhope SE PHARMA J-1802).
• lecithin examples include soybean lecithin.
• the polyoxyethylene polyoxypropylene glycol is preferably the one having an average degree of polymerization of the propylene oxide of 5 and an average degree of polymerization of the ethylene oxide of 105 (PEP-101), or the one having an average degree of polymerization of the propylene oxide of 30 and an average degree of polymerization of the ethylene oxide of 160 (Pluronic F68).
• sorbitan fatty acid esters include sorbitan monolaurate, sorbitan sesquioleate, sorbitan monostearate, and sorbitan monooleate, and the preferred is sorbitan monolaurate.
• propylene glycol fatty acid esters include propylene glycol dicaprylate, propylene glycol monocaprylate, and propylene glycol dicaprate, and the preferred is propylene glycol dicaprylate.
• saturated fatty acid containing 12 to 22 carbon atoms examples include stearic acid, myristic acid, and palmitic acid, and the preferred is stearic acid. Incorporation of such emulsifier prevents oxidation of the polyunsaturated fatty acid in the jelly composition, and hence, the polyunsaturated fatty acid will be stable.
• emulsifiers may be used alone or in combination of two or more.
• use of polyoxyethylene polyoxypropylene glycol in a content of 0.1 to 10% by weight is preferable.
• the preferable combinations include polyoxyethylene polyoxypropylene glycol and at least one member selected from sucrose fatty acid ester, lecithin, sorbitan fatty acid ester, propylene glycol fatty acid ester, and a saturated fatty acid containing 12 to 22 carbon atoms.
• sucrose fatty acid ester lecithin
• sorbitan fatty acid ester propylene glycol fatty acid ester
• a saturated fatty acid containing 12 to 22 carbon atoms a saturated fatty acid containing 12 to 22 carbon atoms.
• Each of these emulsifiers may be incorporated in an amount of 0.1 to 10% by weight.
• One of the particularly preferable combinations of the emulsifiers is a combination of PEP-101 and Surfhope SE PHARMA J-1802.
• Another example of the particularly preferable combination of the emulsifiers is PEP-101, Surfhope SE PHARMA J-1802, and stearic acid.
• Still another example of the particularly preferable combination of the emulsifiers is Pluronic F68 and soybean lecithin.
• Yet another example of the particularly preferable combination of the emulsifiers is PEP-101 and sorbitan monolaurate.
• a further example of the particularly preferable combination of the emulsifiers is PEP-101 and propylene glycol dicaprylate.
• Yet still another example of the particularly preferable combination of the emulsifiers is PEP-101, stearic acid, and propylene glycol dicaprylate.
• the gelling agent incorporated in the jelly composition of the present invention is not particularly limited as long as the merits of the present invention are retained.
• Exemplary gelling agents include carageenan, sodium alginate, guar gum, locust bean gum, tara gum, xanthan gum, cellulose derivative, carboxyvinyl polymer, carmellose sodium, and pullulan, which may be incorporated in a total content of 0.01 to 20% by weight, and preferably 0.1 to 10% by weight. These gelling agents may be used alone or in combination of two or more.
• the gelling agent is the one containing at least one member selected from carageenan, locust bean gum, carmellose sodium, and pullulan, which may be desirably incorporated in a content of 0.05 to 10% by weight. More preferably, the gelling agent is the one containing carageenan, locust bean gum, pullulan, and/or carmellose sodium, which may be desirably incorporated in a content of 0.05 to 10% by weight.
• a preferable embodiment of the jelly composition according to the present invention is the one which has an adequate jelly strength that enables stable storage, high portability, and easy taking, and once taken, which disintegrates in the mouse or in the digestive tract so that the polyunsaturated fatty acid and the second pharmaceutical component are rapidly released in the digestive tract. Such action is realized by using the gelling agent of the present invention.
• Increase in the releasability of the polyunsaturated fatty acid and the second pharmaceutical component can be realized in some cases by reducing the jelly strength to facilitate disintegration of the jelly.
• the jelly strength is too low, the jelly can no longer be taken as a single mass, and some part of the jelly may be left in the container or spilled. In such a case, reliable administration of the predetermined amount of drug is no longer possible.
• the jelly having an excessively high jelly strength will not readily disintegrate in the mouse or in the digestive tract, and it will not form a mass with the saliva, and swallowing will be difficult and may become the cause of aspiration. Accordingly, a jelly having an adequate jelly strength is an example of the jelly which can be easily taken.
• the jelly strength of the jelly composition in the present invention is indicated by the value (breaking strength) obtained by measuring the maximum stress (gf) on the plunger using the following apparatus under the following conditions, and dividing the measured maximum stress by the cross section of the plunger (cm 2 ).
• Inner diameter of the container used for filling the jelly composition 20 mm
• Plunger used columnar shape with a diameter of 10 mm Insertion speed: 30 cm/min Insertion distance: 10 mm
• Temperature room temperature (about 25°C)
• the jelly having an adequate jelly strength is the jelly having a jelly strength (breaking strength) of at least 50 gf/cm 2 and up to 250 gf/cm 2 when the jelly strength is measured by filling the jelly composition in a cylindrical container having an inner diameter of 20 mm by the apparatus as described above, and it is pushed with a columnar plunger having a diameter of 10 mm at an insertion speed of 30 cm/min to an insertion distance of 10 mm at room temperature.
• Such jelly exhibits excellent portability as well as ease of taking with adequate jelly strength so that it can be swallowed at once.
• the jelly adapted for the administration to the so called “bedridden” patients from the tube is preferably a jelly which is easily dispersible in water, and the jelly strength is not particularly limited.
• Exemplary combinations of the emulsifier and the gelling agent include combinations of the emulsifier containing at least one member selected from the group consisting of polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, lecithin, sorbitan fatty acid ester, propylene glycol fatty acid ester, and a saturated fatty acid containing 12 to 22 carbon atoms and a gelling agent containing carageenan, locust bean gum, pullulan, and/or carmellose sodium.
• Preferable content of each component is 0.5 to 5% by weight for polyoxyethylene polyoxypropylene glycol, 0.1 to 3% by weight for sucrose fatty acid ester, 0.1 to 3% by weight for lecithin, 0.1 to 5% by weight for sorbitan fatty acid ester, 0.1 to 5% by weight for propylene glycol fatty acid ester, 0.1 to 5% by weight for a saturated fatty acid containing 12 to 22 carbon atoms, 0.1 to 2% by weight for carageenan, 0.05 to 1% by weight for locust bean gum, 0.5 to 5% by weight for pullulan, and 0.1 to 2% by weight for carmellose sodium.
• a syneresis inhibitor is used to secure long term stability by suppressing syneresis of the jelly composition.
• exemplary syneresis inhibitors include carmellose sodium, pullulan, poly(sodium acrylate), hydroxypropyl methylcellulose, hydroxypropyl cellulose, and crystalline cellulose.
• the syneresis inhibitor is preferably incorporated in an amount of 0.01 to 10% by weight, and more preferably in 0.05 to 5% by weight.
• a content lower than such range is insufficient to show the effect of suppressing the syneresis, whereas a content in excess of such range may invite excessive increase in the viscosity during the preparation rendering production of the homogeneous solution difficult.
• Such syneresis inhibitor may be used alone or in combination of two or more.
• the preferred are carmellose sodium and/or pullulan.
• a gelling aid may be added in order to suppress increase in the viscosity of the emulsion containing the polyunsaturated fatty acid during the preparation stage, for ease of filling in the container, and simultaneously, to improve jelly strength of the cooled jelly composition.
• the gelling aid used may be calcium lactate, potassium chloride, or the like, and the preferred is calcium lactate.
• a gelling aid When a gelling aid is added, it may be incorporated in a content of 0.01 to 10% by weight, and preferably 0.1 to 2% by weight.
• the jelly composition of the present invention may also contain a corrigent (for example, sorbitol, erythritol, maltitol, mannitol, xylitol, or trehalose), a flavoring agent (for example, orange oil, peppermint oil, or apple flavor), a preservatibe (for example, sodium citrate, methyl paraoxybenzoate, or propyl paraoxybenzoate), an antioxidant (for example, tocopherol, tocopherol acetate, propyl gallate, ascorbyl stearate, glycine, sodium ascorbate, or sodium erythorbate), an emulsifier aid (for example, conc.
• a corrigent for example, sorbitol, erythritol, maltitol, mannitol, xylitol, or trehalose
• a flavoring agent for example, orange oil, peppermint oil, or apple flavor
• glycerin or macrogol a pH adjusting agent (for example, citric acid, acetic acid, phosphoric acid, sodium hydrogencarbonate, or sodium hydroxide), a buffer, a colorant, and an antifoaming agent (for example, silicone oil).
• a pH adjusting agent for example, citric acid, acetic acid, phosphoric acid, sodium hydrogencarbonate, or sodium hydroxide
• a buffer for example, a colorant
• an antifoaming agent for example, silicone oil.
• exemplary preferable corrigents include sorbitol, erythritol, xylitol, and trehalose, which may be incorporated in 3 to 30% by weight.
• Exemplary flavoring agents include oily flavors, and in particular, orange oil, which may be incorporated in an amount of 0.01 to 3% by weight.
• Preferred emulsifier aid is conc. glycerin, which may be incorporated in an amount of 2 to 20% by weight.
• the jelly composition of the present invention may be prepared by a method commonly used in the art in preparing a jelly composition as long as the merits of the present invention are retained. More specifically, the jelly composition may be prepared by mixing the polyunsaturated fatty acid, the second pharmaceutical component, the emulsifier, the gelling agent, purified water, and other components in arbitrary order, and homogenizing to allow the mixture to gelate.
• the polyunsaturated fatty acid and the emulsifier are thoroughly mixed with a small amount of water and the emulsifier aid, and the mixture is homogeneously mixed in an agitator.
• This mixture is heated, and a predetermined amount of water is added in small portions for emulsification.
• powder or granular bulk, triturated powder or granule, pulverized commercially available tablet or content of the commercially available capsule, solution, suspension, emulsion, or the like of the second pharmaceutical component is added, and the mixture is homogeneously mixed by using an agitator.
• the gelling agent is added optionally with the gelling aid, and the mixture is heated and vigorously agitated for homogenization.
• a dose of this solution is filled in an appropriate container, and the jelly is formed by cooling.
• the container of the jelly composition is not particularly limited for its shape as long as the jelly composition can be filled, and the thus filled jelly composition can be readily administered.
• Exemplary containers include cup-shaped or tubular containers.
• the preferred is an elongated container formed from a heat sealable laminate film.
• a more preferable embodiment of the container is an elongated container having a gas filled at an end so that the jelly composition can be pushed out of the container at once by cutting an end of the laminate film and pushing the gas from both sides.
• Amount of the jelly composition filled in one container is preferably in the range of 0.5 to 10 g, and more preferably 1 to 6 g.
• An embodiment of the present invention is the jelly composition which has been individually packaged by the process as described above so that one dose of the jelly composition is retained in one container. Since the polyunsaturated fatty acid is susceptible to oxidation during the production, at least a part of the production process is preferably conducted in nitrogen atmosphere, and it is more preferable to conduct all production process in nitrogen atmosphere. By conducting the production under such fully controlled conditions, peroxide value (POV) of the polyunsaturated fatty acid immediately after the production of the jelly composition can be reduced to the level of up to 10 meq/kg.
• POV peroxide value
• the jelly composition of the present invention is well adapted for use as food, health food, food with health claims (food with nutrient function claims and food for specified health use), pharmaceutical preparation, and the like, and more specifically, as an orally administered pharmaceutical preparation.
• the jelly composition of the present invention is particularly suitable for use in a patient with less ability of swallowing or a patient who is allowed to take only limited amount of water.
• the jelly composition of the present invention can be taken once to several times a day at any timing such as just after getting up, before, during, after, or between meals, or before going to bed as food, health food, food with health claims, pharmaceutical preparation, or the like.
• a combination of a jelly composition not containing the second pharmaceutical component and the jelly composition of the present invention, or a combination of different jelly compositions of the present invention each having different formulation may be prepared as a set that can be taken or administered in one day.
• the corrigent and the flavoring agent, shape of the jelly composition, package design and the like can be adequately changed for each jelly composition.
• the term "metabolic syndrome” designates a complication of a series of pathological conditions including obesity, hyperlipidemia, hypertension, and diabetes. Related concepts such as syndrome X, insulin resistance syndrome, visceral fat syndrome, and multiple risk factor syndrome are also included in the "metabolic syndrome" as used in the present invention.
• prevention of the metabolic syndrome means prevention or delaying of occurrence of the symptoms in at least two pathological conditions selected from the group of the pathological conditions as mentioned above.
• treatment of the metabolic syndrome means amelioration or healing of the symptoms in at least two pathological conditions selected from the group of the pathological conditions as mentioned above.
• Components of "A” in Table 1 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and after dissolution, the solution is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 10 mg of pravastatin.
• Table 1 Example 1 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.13 Sucrose fatty acid ester 0.47 Stearic acid 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Pravastatin 0.33 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• a tablet containing 10 mg of cilnidipine (Atelec Tablets 10 manufactured by Ajinomoto Co., Inc. containing 10 mg of cilnidipine in a tablet of about 0.27 g) is pulverized by using a commercially available pulverizer, and a powder containing homogeneously dispersed cilnidipine is preliminarily prepared. Using this powder, the procedure of Example 1 is repeated for the components of Table 2 to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 10 mg of cilnidipine.
• Table 2 Example 2 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.00 Sorbitan monolaurate 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Cilnidipine 0.33 (in terms of cilnidipine bulk) Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Example 3 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.53 Propylene glycol dicaprylate 0.87 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Candesartan 0.40 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Example 4 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.60 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Pioglitazone 1.5 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Example 5 Components of "A” in Table 5 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and after dissolution, components of "D” are added. Using this solution, the procedure of Example 1 is repeated to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 3 mg of donepezil. [Table 5] Table 5: Example 5 Components Content (% by weight) A Polyoxyethylene (160) polyoxypropylene (30) glycol 2.02 Soybean lecithin 0.38 Conc.
• Example 6 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.53 Propylene glycol dicaprylate 0.87 Stearic acid 0.50 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Atorvastatin 0.17 Amlodipine 0.17 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Example 7 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 2.02 Sucrose fatty acid ester 0.84 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 30.00 Simvastatin 0.33 Voglibose 0.03 Sodium hydroxide q.s. Purified water q.s. C Trehalose 7.50 Carageenan 0.49 Locust bean gum 0.25 Pullulan 1.50
• the jelly compositions of Examples 1 to 7 exhibit no change in the shape or occurrence of syneresis.
• the jelly compositions of Examples 1 to 7 are tested by a method based on the paddle method defined for the dissolution test in the Japanese Pharmacopeia (International Journal of Pharmaceutics, vol. 95, pp. 67 to 75 ) which involves introducing 160 mL of an artificial gastric juice (an aqueous solution containing 115 mmol/L of sodium chloride and 35 mmol/L of potassium chloride which had been adjusted with hydrochloric acid to a pH of 2.5) serving as a test solution as well as 2000 nylon beads (diameter, 6.4 mm) in a beaker for use in a dissolution tester and stirring at a temperature of 37°C and a paddle rotation rate of 25 to evaluate the release of the ethyl icosapentate and the second pharmaceutical component into the test solution, the jelly compositions of Examples 1 to 7 exhibit excellent release.
• an artificial gastric juice an aqueous solution containing 115 mmol/L of sodium chloride and 35 mmol/L of potassium chloride which had been
• the jelly compositions of Examples 1 to 6 exhibit excellent increases of the blood concentrations for both the EPA and the second pharmaceutical component.
• the value (breaking strength) is obtained by measuring the maximum stress (gf) on the plunger using the following apparatus under the following conditions, and dividing the measured maximum stress by the cross section of the plunger (cm 2 ).
• Temperature room temperature (about 25°C)
• the jelly compositions of Examples 1 to 7 have a jelly strength of 10 to 250 gf/cm 2 .
• Components of "A” in Table 8 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and the preparation obtained after homogenization is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate.
• Table 8 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.13 Sucrose fatty acid ester 0.47 Stearic acid 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Components of "A” in Table 9 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and the preparation obtained after homogenization is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 10 mg of pravastatin sodium.
• Table 9 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.13 Sucrose fatty acid ester 0.47 Stearic acid 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Pravastatin sodium 0.33 Purified water 15.00 B Ethyl icosapentate 20.00 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Components of "A” in Table 10 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and the preparation obtained after homogenization is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 10 mg of simvastatin.
• Table 10 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.13 Sucrose fatty acid ester 0.47 Stearic acid 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Simvastatin 0.33 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• the jelly compositions of Reference Example 1 and Examples 8 and 9 are observed for their appearance and the pH is also measured. These compositions are also evaluated for their jelly strength by the procedure as described above. As an example, the results are shown in Table 11.
• the jelly compositions of Examples 8 and 9 containing the second pharmaceutical component had substantially the same appearance and pH as those of the jelly composition of Reference Example 1 not containing the second pharmaceutical component, as well as a jelly strength in the range of 50 to 250 gf/cm 2 which is appropriate for use as a pharmaceutical product.
• Table 11 Appearance pH Jelly strength (gf/cm 2 ) Reference Example 1 Slightly yellowish white jelly 5.56 183 Example 8 Slightly yellowish white jelly 5.58 148 Example 9 Slightly yellowish white jelly 5.63 129
• Components of "A” in Table 12 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and the preparation obtained after homogenization is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate.
• Table 12 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.00 Sorbitan monolaurate 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Components of "A” in Table 13 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and the preparation obtained after homogenization is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 10 mg of pravastatin sodium.
• Table 13 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.00 Sorbitan monolaurate 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Pravastatin sodium 0.33 Purified water 15.00 B Ethyl icosapentate 20.00 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• Components of "A” in Table 14 are weighed, mixed, and heated to 80°C for dissolution in nitrogen atmosphere (oxygen concentration, up to 0.2%). To this mixture are added components of "B”, and the mixture is emulsified by high speed agitation. Components of "C” are then added, and the preparation obtained after homogenization is filled in an elongated pouch of a laminate film at about 3 g/pouch. After heat sealing, it is cooled to prepare a jelly composition containing about 600 mg of ethyl icosapentate and about 10 mg of simvastatin.
• Table 14 Components Content (% by weight) A Polyoxyethylene (105) polyoxypropylene (5) glycol 1.00 Sorbitan monolaurate 1.00 Conc. glycerin 7.50 Ascorbyl stearate 0.02 Sodium erythorbate 1.30 Orange oil 0.90 Purified water 15.00 B Ethyl icosapentate 20.00 Simvastatin 0.33 Sodium hydroxide q.s. Purified water q.s. C Trehalose 15.00 Carageenan 0.42 Locust bean gum 0.25 Pullulan 3.00
• the jelly compositions of Reference Example 2 and Examples 10 and 11 are observed for their appearance and the pH is also measured. These compositions are also evaluated for their jelly strength by the procedure as described above. As an example, the results are shown in Table 15.
• the jelly compositions of Examples 10 and 11 containing the second pharmaceutical component had substantially the same appearance and pH as those of the jelly composition of Reference Example 2 not containing the second pharmaceutical component, as well as a jelly strength in the range of 50 to 250 gf/cm 2 which is appropriate for use as a pharmaceutical product.
• Table 15 Appearance pH Jelly strength (gf/cm 2 ) Reference Example 2 Slightly yellowish white jelly 7.29 186 Example 10 Slightly yellowish white jelly 7.37 179 Example 11 Slightly yellowish white jelly 7.07 188

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Diabetes (AREA)
• Organic Chemistry (AREA)
• Emergency Medicine (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Zoology (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Endocrinology (AREA)
• Child & Adolescent Psychology (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (3)

Publications (3)

Family

ID=38023321

Family Applications (1)

Country Status (8)

Cited By (26)

Families Citing this family (22)

Citations (2)

Family Cites Families (19)

• 2006
  • 2006-11-10 US US12/084,643 patent/US8962682B2/en not_active Expired - Fee Related
  • 2006-11-10 EP EP06823305.5A patent/EP1946755B1/fr not_active Not-in-force
  • 2006-11-10 CN CN2006800425683A patent/CN101309679B/zh not_active Expired - Fee Related
  • 2006-11-10 CA CA2628305A patent/CA2628305C/fr not_active Expired - Fee Related
  • 2006-11-10 WO PCT/JP2006/322483 patent/WO2007055327A1/fr active Application Filing
  • 2006-11-10 BR BRPI0618455-3A patent/BRPI0618455A2/pt not_active IP Right Cessation
  • 2006-11-10 KR KR1020087013598A patent/KR101292573B1/ko active IP Right Grant
  • 2006-11-10 JP JP2007544200A patent/JP5113527B2/ja not_active Expired - Fee Related

Patent Citations (2)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events